Autoinhibition can identify rare driver mutations and advise pharmacology

Abstract

Identification of protein mutations that drive cancer is a major challenge. A primary reason is that driver mutations are principally identified by their high frequency even though they can also be rare. Driver mutations can locate at functional (binding or active) sites. We dub these orthosteric drivers. However, often they are allosteric drivers. Identification is particularly formidable for rare allosteric drivers. Autoinhibition, where a segment of the protein covers its functional site, is a common allosteric regulation mechanism. A modest shift in the equilibrium can switch the system from the autoinhibited to the active state. This can suggest why (i) mutations are likely to evolve to target it; (ii) inhibitors can straightforwardly relieve the autoinhibition but not vice versa; and why (iii) mutations that relieve the autoinhibition are likely to be drivers—even if they are rare. We explain in simple terms the linkage between allosteric driver mutations, release of autoinhibition, free energy landscapes, and targeted pharmacology in precision medicine. We review the literature and propose new concepts in identification of rare drivers in this framework.

B-Raf autoinhibition in the presence and absence of 14-3-3

“…B-Raf autoinhibition in the absence of the 14-3-3 dimer In the absence of the 14-3-3 dimer, B-Raf can also be autoinhibited through the association of RBD-CRD and KD, which indicates another autoinhibition scenario. The interactions between RBD-CRD and KD are expected to be metastable, in line with the principles of autoinhibition (Nussinov et al, 2018(Nussinov et al, , 2020. To date no structure is available.…”

“…Like all kinases, wild-type Raf is expected to spend most of its lifetime in the inactive state. The monomeric ''closed'' autoinhibited state guards against spurious activation and signaling, as well as degradation, by shielding the KD dimerization surface (Nussinov et al, 2020). Extensive data indicate the involvement of 14-3-3 proteins in Raf autoinhibition (Kondo et al, 2019;Liau et al, 2020;Park et al, 2019).…”

Multiple domain interfaces mediate SARM1 autoinhibition

“…Our findings here in conjunction with prior studies (27,34) suggest that relief of autoinhibition likely entails the release of the TIR domain from the interaction with ARM domains intramolecularly and intermolecularly. Posttranslational modifications and ligand binding are rapid and local mechanisms to relieve autoinhibition in other proteins (24)(25)(26); however, the hydrophobic nature of the major ARM region that suppresses the TIR domain through direct interaction makes this region a poor candidate for modification or even ligand binding. Instead, we hypothesize that sensing of an injury-induced cue occurs at a site away from the direct ARM-TIR interfaces.…”

“…To control this prodegenerative activity, SARM1 regulation must incorporate two key features: 1) enzymatic activity must be inhibited in healthy neurons, and 2) injury-or disease-induced prodegenerative signals must relieve this autoinhibition. Autoinhibition is a common mechanism for tightly controlling protein activity, effectively maintaining an "off" state at equilibrium and rapidly responding to stimuli to induce the "on" state (24)(25)(26). The N-terminal ARM domain is required for autoinhibition of SARM1, as deletion mutants lacking the entire N terminus are constitutively active, leading to spontaneous axon degeneration (5).…”

Nucleotide-Specific Autoinhibition of Full-Length K-Ras4B Identified by Extensive Conformational Sampling

“…Autoinhibition protects against spurious activation and proteolysis (reviewed in Nussinov et al, 2018 ). Even if the interaction of the autoinhibiting segment is weak, its large population at the active/functional site effectively shields it, which explains why oncogenic drivers often aim to release it (Nussinov et al, 2020 ).…”